Functional and physiological role of vitamin C transporters

Vitamin C (ascorbic acid) is required for the synthesis of collagen, carnitine, catecholamine and the neurotransmitter norepinephrine. Vitamin C also plays an important role in protection against oxidative stress. Transporters for vitamin C and its oxidized form dehydroascorbate (DHA) are crucial to keep vitamin concentrations optimal in the body. The human SLC23 family consists of the Na(+)-dependent vitamin C transporters SVCT1 (SLC23A1) and SVCT2 (SLC23A2) and the orphan transporter SVCT3 (SLC23A3). Phylogenetically, the SLC23 family belongs to the nucleobase-ascorbate transporter family although no specificity for nucleobases has yet been demonstrated for the human members of this family. In fact, the SVCT1 and SVCT2 transporters are rather specific for ascorbic acid. SVCT1 is expressed in epithelial tissues such as intestine, where it contributes to the maintenance of whole-body ascorbic acid levels, whereas the expression of SVCT2 is relatively widespread either to protect metabolically active cells and specialized tissues from oxidative stress or to deliver ascorbic acid to tissues that are in high demand of the vitamin for enzymatic reactions. DHA, the oxidized form of ascorbic acid is taken up and distributed in the body by facilitated transport via members of the SLC2/GLUT family (GLUT1, GLUT3, and GLUT4). Although, the main focus of this review is on the SLC23 family of ascorbic acid transporters, transporters of DHA and nucleobases are also briefly discussed for completeness.

Screening for sleep disorders in community pharmacies--evaluation of a campaign in Switzerland

BACKGROUND: In 2003 the Swiss federation of pharmacists organized a campaign "sleep disturbances--daytime sleepiness". The goal was to assist pharmacy clients in detecting likely causes of any sleep disturbance or daytime sleepiness through a free of charge screening, and to deliver targeted counselling. For pharmacy practice there are no screening or triage guidelines to assess the severity of sleep and wakefulness disturbances and potential causes for those disturbances. In this paper the outcome of the campaign in terms of feasibility, participation, observed response patterns, sale of over-the-counter (OTC) sleeping pills, and counselling activities is evaluated. METHODS: The Stanford sleep disorders questionnaire and the Epworth sleepiness scale served to identify patterns of symptoms suggestive of four major categories of sleep disorders. The questionnaires were posted on a web-site and the clients' data were entered online in the pharmacies. A report was automatically generated and immediately available online to the pharmacists. The pharmacists documented separately their counselling activities in a pharmacist's activity report. RESULTS: Six hundred and twenty-two (23%) of 2743 pharmacy clients had response patterns suggestive of obstructive sleep apnoea, 418 (15%) of restless-legs-syndrome, 39 (1%) of a sleep disorder potentially associated with a psychiatric condition and 79 (3%) of narcolepsy. An Epworth sleepiness score >10 points was found in 567 (21%). After screening, 2345 (86%) pharmacy clients received targeted counselling. Only 216 (8%) purchased an OTC sleeping pill and 704 (26%) were recommended to consult a physician, but of these, 446 (63%) were already under medical supervision. CONCLUSIONS: The online screening tool for sleep disorders and daytime sleepiness was successfully introduced in Swiss pharmacies. Pharmacies were able to assess the pattern of individual sleep disorders and to identify a possible cause in nearly one-third of the cases.

Association of lipopolysaccharide-binding protein and coronary artery disease in men

OBJECTIVES: In this study we tested the hypothesis that lipopolysaccharide-binding protein (LBP) might be able to be used as a biomarker for coronary artery disease (CAD). BACKGROUND: The mechanisms by which the innate immune recognition of pathogens could lead to atherosclerosis remain unclear. Lipopolysaccharide-binding protein is the first protein to encounter lipopolysaccharide and to deliver it to its cellular targets, toll-like receptors; therefore, its presence might be a reliable biomarker that indicates activation of innate immune responses. METHODS: A total of 247 men undergoing elective coronary angiography were studied, and the extent of coronary atherosclerosis was assessed by 2 established scores: "extent score" and "severity score." Levels of LBP, markers of inflammation, and traditional risk factors for CAD were assessed. RESULTS: Serum LBP concentration was significantly increased in 172 patients with angiographically confirmed CAD compared with 75 individuals without coronary atherosclerosis (20.6 +/- 8.7 pg/ml vs. 17.1 +/- 6.0 pg/ml, respectively; p = 0.002). Moreover in multivariable logistic regression analyses, adjusted for established cardiovascular risk factors and markers of systemic inflammation, LBP was a significant and independent predictor of prevalent CAD (p < 0.05 in all models). CONCLUSIONS: Lipopolysaccharide-binding protein might serve as a novel marker for CAD in men. The present results underlie the potential importance of innate immune mechanisms for CAD. Further studies are warranted to bolster the data and to identify pathogenetic links between innate immune system activation and atherosclerosis.

The laulimalide family: total synthesis and biological evaluation of neolaulimalide, isolaulimalide, laulimalide and a nonnatural analogue

We herein describe in full detail the first total synthesis of the antitumor agents neolaulimalide and isolaulimalide as well as a highly efficient route to laulimalide. A Kulinkovich reaction followed by a cyclopropyl-allyl rearrangement is used to install the exo-methylene group. The C(2)-C(16) aldehyde fragment is coupled with the C(17)-C(28) sulfone fragments by a highly (E)-selective Julia-Lythgoe-Kocienski olefination to deliver the key intermediates of all three syntheses. Various conditions for the Yamaguchi macrolactonization are applied to close the individual macrocycles. Finally a carefully elaborated endgame was developed to solve the problem of acyl migration in the case of neolaulimalide. All compounds were tested against several cell lines. The cytotoxicity of neolaulimalide could be confirmed for the first time since its original isolation and it could be shown that it induces tubulin polymerization as efficiently as laulimalide.

Factors influencing the quality of the consultation process

Sport psychology services have become to be an important brick stone when building athletic success. The strive for better performance is not only a characteristic of athletes, but of the whole support system in top level sport including sport psychology. Sport psychology consultants are permanently challenged to deliver highest quality services to their clients if they do not want to lose their contracts. Sport psychologists are continuously improving their consulting skills, learn new intervention techniques, read scientific papers and, last but not least, gain experience by accumulating hours of deliberate practice (Ericsson) in sport psychology. Even with increasing experience, the consultant has a certain number of degrees of freedom and has to make a series of decisions about how he or she wants to work. Quality, however, depends on a number of issues, and not all of them are under direct control of the consultant. It is argued that, in order for these choices being good, the following factors - among others - must be considered: Who is seeking assistance? What are the "issues and problems" (Gardner & Moore, 2006) the athlete is confronted with? What kind of approaches do fit with the client's need? Who is the 'client' the sport psychologist is supposed to work with? If it is a team, is the sport psychologist supposed to work with a number of individuals, with the coach, or with the whole system? Where are the boundaries of the system? What is the role of the sport psychologist in the sport system? All these issues directly affect the process and outcome quality of the sport psychology consultant. A sound theoretical basis, in connection with a distinct philosophy of the intervention, is an important cornerstone for the quality of sport psychology consultation.

The Advantages of Parametric Modeling for the Reconstruction of Historic Buildings

Consecrated in 1297 as the monastery church of the four years earlier founded St. Catherine’s monastery, the Gothic Church of St. Catherine was largely destroyed in a devastating bombing raid on January 2nd 1945. To counteract the process of disintegration, the departments of geo-information and lower monument protection authority of the City of Nuremburg decided to getting done a three dimensional building model of the Church of St. Catherine’s. A heterogeneous set of data was used for preparation of a parametric architectural model. In effect the modeling of historic buildings can profit from the so called BIM method (Building Information Modeling), as the necessary structuring of the basic data renders it into very sustainable information. The resulting model is perfectly suited to deliver a vivid impression of the interior and exterior of this former mendicant orders’ church to present observers.

The transpedicular approach as an alternative route for intervertebral disc regeneration

STUDY DESIGN Descriptive anatomical study on ovine and human cadaveric lumbar spinal segments. OBJECTIVE To describe the alternative transpedicular approach to deliver therapeutic agents into intervertebral disc (IVD). SUMMARY OF BACKGROUND DATA The present delivery approach of therapeutic agents (growth factors/cells/hydrogels) within the IVD is through injection, via the annulus fibrosus (AF). However, it has recently been demonstrated that small needle puncture of the AF leads to further degeneration and disc herniation. In addition, the injected material has a high chance to be extruded through the AF injury. METHODS Lumbar ovine and human spinal segments were used. Under fluoroscopy, a 2-mm Kirschner wire was introduced in the caudal vertebra through the pedicle and the inferior endplate to the nucleus pulposus. Gross anatomy analysis and high-resolution peripheral quantitative computed tomography (HR-pQCT) were performed to assess the right position of the wire in pedicles. Discography and nucleotomy were performed using a 14G cannula insertion or a 2-mm arthroscopic shaver blade, respectively. Nucleoplasty was also performed with agarose gel/contrast agent and imaged with HR-pQCT. RESULTS Gross anatomy, fluoroscopy, and HR-pQCT images showed that the nucleus pulposus could be approached through the endplate via the pedicle without affecting the spinal canal and the neural foramina. The contrast agent was delivered into the IVD and nucleus pulposus was removed from the disc and filled with agarose gel. CONCLUSION This study describes how a transpedicular approach can be used as an alternative route to deliver therapeutic agents to the disc without disruption of the AF showing the potential use of this technique in preclinical research and highlighting its clinical relevance for IVD regeneration.

Directional deep brain stimulation: an intraoperative double-blind pilot study.

Deep brain stimulation of different targets has been shown to drastically improve symptoms of a variety of neurological conditions. However, the occurrence of disabling side effects may limit the ability to deliver adequate amounts of current necessary to reach the maximal benefit. Computed models have suggested that reduction in electrode size and the ability to provide directional stimulation could increase the efficacy of such therapies. This has never been demonstrated in humans. In the present study, we assess the effect of directional stimulation compared to omnidirectional stimulation. Three different directions of stimulation as well as omnidirectional stimulation were tested intraoperatively in the subthalamic nucleus of 11 patients with Parkinson's disease and in the nucleus ventralis intermedius of two other subjects with essential tremor. At the trajectory chosen for implantation of the definitive electrode, we assessed the current threshold window between positive and side effects, defined as the therapeutic window. A computed finite element model was used to compare the volume of tissue activated when one directional electrode was stimulated, or in case of omnidirectional stimulation. All but one patient showed a benefit of directional stimulation compared to omnidirectional. A best direction of stimulation was observed in all the patients. The therapeutic window in the best direction was wider than the second best direction (P = 0.003) and wider than the third best direction (P = 0.002). Compared to omnidirectional direction, the therapeutic window in the best direction was 41.3% wider (P = 0.037). The current threshold producing meaningful therapeutic effect in the best direction was 0.67 mA (0.3-1.0 mA) and was 43% lower than in omnidirectional stimulation (P = 0.002). No complication as a result of insertion of the directional electrode or during testing was encountered. The computed model revealed a volume of tissue activated of 10.5 mm(3) in omnidirectional mode, compared with 4.2 mm(3) when only one electrode was used. Directional deep brain stimulation with a reduced electrode size applied intraoperatively in the subthalamic nucleus as well as in the nucleus ventralis intermedius of the thalamus significantly widened the therapeutic window and lowered the current needed for beneficial effects, compared to omnidirectional stimulation. The observed side effects related to direction of stimulation were consistent with the anatomical location of surrounding structures. This new approach opens the door to an improved deep brain stimulation therapy. Chronic implantation is further needed to confirm these findings.

Influences of porcine circo-, arteriviruses and cathelicidins in plasmacytoid dendritic cell-derived interferon-alpha responses

Type I interferons (IFNs), mainly IFN-α/β play a crucial role in innate defense against viruses. In addition to their direct antiviral activity, type I IFNs have antitumoral and immunomodulatory effects. Although all cells are virtually able to induce IFN-α, the plasmacytoid dendritic cell (pDC) subset represents the ultimate producers of IFN-α as well as other proinflammatory cytokines. Due to the specific expression of TLR7 and TLR9 recognizing single-stranded (ss) RNA and unmethylated CpG motifs respectively, pDCs can secrete up to 1000 times more IFN-α than any cellular types. Additionally, it is well known that several cytokines including type I and II IFNs, Flt3-L, IL-4 and GM-CSF favor pDC-derived IFN-α responses to unmethylated CpG motifs. In a first step, we aimed to characterize and clarify the interactions of two porcine viruses with pDCs. The double-stranded DNA replicative forms of porcine circovirus type 2 (PCV2) were demonstrated to inhibit CpG-induced IFN- α by pDCs. Our study showed that none of the cytokines known to enhance pDC responsiveness can counter-regulate the PCV2-mediated inhibition of IFN-α induced by CpG, albeit IFN-γ significantly reduced the level of inhibition. Interestingly, the presence of IFN-γ enabled pDCs to induce IFN-α to low doses of PCV2. We also noted that after DNase treatment, PCV2 preparations were still able to stimulate pDCs. These data suggest that encapsulated viral ssDNA promotes the induction of IFN-α in pDCs treated with IFN-γ whereas free DNA, presumably as double-stranded forms, was responsible for inhibiting pDC responses. Regarding PRRSV, it has been reported that North American isolates did not induce and even inhibited IFN-α response in pDCs. However, PRRSV infection was also shown to lead to an induction of IFN-α in the serum and in the lungs suggesting that certain cells are responsive to the virus. Contrasting to previous reports we found that numerous PRRSV isolates directly induced IFN-α in pDCs. This response was still observed after UV-inactivation of viruses and required TLR7 signaling. The inhibition of CpG-induced IFN-α was weak and strain dependent, again contrasting with a previous report. We also observed that IFN-γ and IL-4 enhanced IFN-α response to two prototype strains, VR-2332 and LVP23. In summary, we demonstrated that both PCV2 and PRRSV promote IFN-α secretion in pDCs in vitro suggesting that IFN-α detected in PCV2- or PRRSV-infected animal might originate from pDCs. On the other hand, PRRSV replication is restricted to the macrophage (MΦ) lineage. These innate immune cells represent a heterogeneous population which can be induce to “classical” (M1) and “alternative” (M2) activated MΦ acquiring inflammatory or “wound-healing” functional properties, respectively. Nonetheless, little is known about the effect of polarization into M1 or M2 and the susceptibility of these cells to PRRSV. Thus, we examined the impact of cytokine on MΦ polarization into M1 or M2. Infections of these cells by several PRRSV isolates enabled the discrimination of PRRSV isolate in a genotype- and irulencedependent manner in M1 and IFN-β-activated MΦ. In contrast, the expression of PRRSV nucleocapsid in M2 or inactivated MΦ was indistinguishable among the PRRSV isolates tested. In the last part of my Thesis, we investigated the influence of three synthetic porcine cathelicidin peptides for their ability to deliver nucleic acid to pDCs. We reported that all cathelicidins tested can complex and quickly deliver nucleic acids resulting in IFN-α induction. Moreover, we show that the typical α- helical amphipathic conformation is required to mediate killing of bacteria but not for inducing IFN-α secretion by pDCs. Furthermore, we found that E.coli treated with one of these cathelicidins is able to induce significantly higher levels of IFN-α compared to a non-sense version of the peptide. These data suggest that cathelicidins could influence the immune response in a two-step process. First, these peptides target bacteria leading to cell lysis. In turn, cathelicidins form complexes and deliver extracellular microbial nucleic acids released into pDCs. These pDC-derived IFN-α responses could be of particular relevance in driving the adaptive immune responses against microbial infections.

Influence of hormone replacement therapy on proteomic pattern in serum of postmenopausal women

OBJECTIVES: Proteomics approaches to cardiovascular biology and disease hold the promise of identifying specific proteins and peptides or modification thereof to assist in the identification of novel biomarkers. METHOD: By using surface-enhanced laser desorption and ionization time of flight mass spectroscopy (SELDI-TOF-MS) serum peptide and protein patterns were detected enabling to discriminate between postmenopausal women with and without hormone replacement therapy (HRT). RESULTS: Serum of 13 HRT and 27 control subjects was analyzed and 42 peptides and proteins could be tentatively identified based on their molecular weight and binding characteristics on the chip surface. By using decision tree-based Biomarker Patternstrade mark Software classification and regression analysis a discriminatory function was developed allowing to distinguish between HRT women and controls correctly and, thus, yielding a sensitivity of 100% and a specificity of 100%. The results show that peptide and protein patterns have the potential to deliver novel biomarkers as well as pinpointing targets for improved treatment. The biomarkers obtained represent a promising tool to discriminate between HRT users and non-users. CONCLUSION: According to a tentative identification of the markers by their molecular weight and binding characteristics, most of them appear to be part of the inflammation induced acute-phase response

A Case for CDN-as-a-Service in the Cloud: A Mobile Cloud Networking Argument

Content Distribution Networks are mandatory components of modern web architectures, with plenty of vendors offering their services. Despite its maturity, new paradigms and architecture models are still being developed in this area. Cloud Computing, on the other hand, is a more recent concept which has expanded extremely quickly, with new services being regularly added to cloud management software suites such as OpenStack. The main contribution of this paper is the architecture and the development of an open source CDN that can be provisioned in an on-demand, pay-as-you-go model thereby enabling the CDN as a Service paradigm. We describe our experience with integration of CDNaaS framework in a cloud environment, as a service for enterprise users. We emphasize the flexibility and elasticity of such a model, with each CDN instance being delivered on-demand and associated to personalized caching policies as well as an optimized choice of Points of Presence based on exact requirements of an enterprise customer. Our development is based on the framework developed in the Mobile Cloud Networking EU FP7 project, which offers its enterprise users a common framework to instantiate and control services. CDNaaS is one of the core support components in this project as is tasked to deliver different type of multimedia content to several thousands of users geographically distributed. It integrates seamlessly in the MCN service life-cycle and as such enjoys all benefits of a common design environment, allowing for an improved interoperability with the rest of the services within the MCN ecosystem.

Retirement as a “language related major life event” and its consequences on the multilingualism of migrants

The present study investigates life stories of established Italian workforce migrants living in the city of Berne, Switzerland, in regard to “language related major life events” (De Bot, 2007). These events are important in terms of changes happening in the linguistic setting during the life span and influence language development. In this sense, during the process of retirement, a new phase of life begins, which, amongst other things, has to be reorganized in relation to social contact and language use. One of my main questions is how the subjects handle the changes happening within and after the process of retirement in respect to the use of different languages and how this “language related major life event” is constructed and described by the migrants. One of these changes happens due to the fact that, after retirement, the social network at the workplace (the primary source of language input) can get (partially) lost and with it, the use of the local language. The fact that migrants living in Berne are confronted with diglossia (Standard German and Swissgerman), that the Canton of Berne is bilingual (German and French) and that the migrants' mother tongue (Italian) is one of the Swiss national languages, makes this question even more interesting. A second question will consider the influence of the fact that most of the subjects in question lived with the idea of return migration, but as shown in a previous study (Alter/Vieillesse/Anziani, NFP 32, 1999), only a third returned back while another third remained in the host country and the final third chose the commuting option. I will first examine these processes, changes and influences by using quantitative questionnaires in order to obtain general information on demographic data, the social situation, and a self-assessment of linguistic skills. Secondly, I will use qualitative interviews to get in-depth information of the subjects’ life stories and language biographies. The results of this project are meant to deliver insight into different aspects that have not been looked at in detail to this point: which factors of the life stories of Italian workforce migrants, who decided to remain in Switzerland after retirement, influence the linguistic changes in general and the ones happening around retirement in particular.

Feasibility of Information-Centric Networking Integration into LTE Mobile Networks

With the current growth of mobile devices usage, mobile net- works struggle to deliver content with an acceptable Quality of Experience. In this paper, we propose the integration of Information Centric Networking into 3GPP Long Term Evolution mobile networks, allowing its inherent caching feature to be explored in close proximity to the end users by deploying components inside the evolved Node B. Apart from the advantages brought by Information-Centric Networking’s content requesting paradigm, its inherent caching features enable lower latencies to access content and reduce traffic at the core network. Results show that the impact on the evolved Node B performance is low and ad- vantages coming from Information-Centric Networking are considerable. Thus, mobile network operators reduce operational costs and users end up with a higher perceived network quality even in peak utilization periods.

Peptide receptor radionuclide therapy for patients with somatostatin receptor expressing tumours. German Guideline (S1).

This document describes the guideline for peptide receptor radionuclide therapy (PRRT) published by the German Society of Nuclear Medicine (DGN) and accepted by the Association of the Scientific Medical Societies in Germany (AWMF) to be included in the official AWMF Guideline Registry. These recommendations are a prerequisite for the quality management in the treatment of patients with somatostatin receptor expressing tumours using PRRT. They are aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRT and to deliver the treatment in a safe and effective manner. The recommendations are based on an interdisciplinary consensus. The document contains background information and definitions and covers the rationale, indications and contraindications for PRRT. Essential topics are the requirements for institutions performing the therapy, e. g. presence of an expert for medical physics, intense cooperation with all colleagues involved in the treatment of a patient, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with the involved medical disciplines. Generally, the decision for PRRT should be undertaken within the framework of a multi-disciplinary tumour board.

Natural Resources in 2025 - Implications for Development : Opportunity of a trunaround: An expert reassessment

In recent years developing countries have faced highly dynamic changes affecting their natural resource base and their potential for development. Taking into account these changes in the development context, InfoResources initiated a critical reassessment of the results of InfoResources Trends 2005 and again invited experts from around the world to assess trends that least developed countries are likely to be facing by 2025. The unanimous signal conveyed by the international experts for this assessment is alarming: The degradation of natural resources is progressing. By 2025 it will reach a point where livelihoods in least developing countries will be significantly threatened and an increasing number of agro-ecosystems will lose their capacity to deliver important services. Expected positive social trends will not suffice as leverage to reverse the degradation of natural resources and thus alleviate poverty and hunger. However, the present reassessment clearly reveals that a change in thinking and a shift in paradigms have begun to take place. However, a turnaround can only succeed if the emerging awareness of the need to reorient policy-making and the economy is followed by concrete action. It will be crucial that policies and institutions regain regulating power over greedy economic forces. This reassessment does not claim to be comprehensive. However, the present publication, which synthesises the experts’ inputs, aims at providing food for thought and initiating discussions.